Figure 1. Endosomal trafficking and signaling dysregulation as a potential pathogenic mechanism in CMT and other diseases that involve SIMPLE dysfunction. (A) Domain structure of SIMPLE and mutations found in CMT1C patients. PSAP, predicted TSG101-binding site; PPSY, predicted NEDD4-binding site; C-rich domain, cysteine-rich domain; TMD, predicted transmembrane domain. The locations of CMT1C-linked SIMPLE mutations are indicated on the domain structure. (B) Potential pathogenic roles of SIMPLE dysfunction in CMT, cancer, obesity and inflammatory bowel diseases. Our recent work²⁴ suggests a pathogenic pathway by which CMT1C-linked SIMPLE mutations^2-6 cause demyelinating peripheral neuropathy by disrupting endosome-to-lysosome trafficking and signaling attenuation of NRG1-activated ErbB2/ErbB3 receptors and consequently prolonging their signaling to downstream pathways in Schwann cells (colored in pink). Downregulation of SIMPLE expression found in several types of cancer^11-14 may contribute to the process of malignant transformation by impairing endosome-to-lysosome trafficking and signaling attenuation of mitogenic signaling receptors (colored in lavender). Upregulation of SIMPLE expression found in obesity¹⁵ and inflammatory bowel diseases¹⁶ may contribute to the pathogenesis or progression of these diseases by altering endosomal trafficking and intracellular signaling (colored in blue).